The objective of this research is to define the pathogenesis of the biochemical abnormalities that occur in the porphyrias, which are inherited disorders of heme metabolism. Particular attention is paid to protoporphyria, which is characterized by the excessive accumulation and excretion of protoporphyrin. We have shown that the activity of heme synthase, which catalyzes the chelation of iron to protoporphyrin, is deficient in tissues of patients with protoporphyria and are now using cultured skin fibroblasts to define the enzymatic defect. Other disorders of protoporphyrin are also being investigated. In bovine protoporphyria, an inherited disease in cattle in which the biochemical abnormalities are the same as in human protoporphyria, heme synthase activity is being measured in cultured skin fibroblasts and other tissues in order to draw comparisons with the human disease. The possibility that heme synthase and/or protoporphyrinogen oxidase is defective in tissue of patients with variegate porphyria is being examined, since these patients have increased fecal excretion of protoporphyrin. The reason why the zinc chelate of protoporphyrin accumulates in red cells of patients with lead poisoning and iron deficiency, whereas free protoporphyrin accumulates in patients with protoporphyria, is also being studied.